Diabetes is a metabolic disease, which causes a problem in insulin secretion or insulin function due to genetic or environmental reasons and thus the glucose in the blood cannot be utilized as an energy source for cells, thereby showing the symptoms of hyperglycemia having high blood glucose levels. Diabetes can cause complications and is one of the most serious chronic diseases in modern society.
Diabetes can be largely classified into type 1 diabetes and type 2 diabetes. Type 1 diabetes accounts for less than 10% of the total diabetic patients and mostly occurs in children. Reportedly, type 1 diabetes occurs when the pancreatic β cells fail to produce or secrete insulin by their destruction due to auto-immune diseases, etc., and thus type 1 diabetic patients require lifetime insulin injections. In contrast, type 2 diabetes accounts for 90% or more of the total diabetic patients and mostly occurs in adults, and in particular, more frequently in overweight and obese adults. Reportedly, type 2 diabetes is caused by defective insulin secretion or insulin resistance in the pancreas.
For the treatment of diabetes, people usually start with physical exercise and diet therapy. However, when these efforts fail to control the blood glucose levels, a single or combined diabetic agent may be administered. According to the American Diabetes Association (ADA) guidelines, the first-selection drug is metformin, the second- and third-selection drugs include sulfonylurea-based, glinide-based, thiazolidinedione-based, DPP-4 inhibitors, etc., and injections, such as a glucagon like peptide-1 (GLP-1) agonist, or insulin injections are followed thereafter.
The conventional oral therapeutic agents currently used in clinical treatment have the advantage of capable of continuously maintaining normal blood glucose levels, however, the long-term administration of these agents not only causes various adverse effects such as causing hypoglycemia, diarrhea, body weight gain, cardiovascular problems, hepatotoxicity, etc., but also causes destruction of the pancreatic β cells, thereby ultimately requiring an insulin injection. Additionally, the insulin injection, as the final treatment, must be administered subcutaneously two to three times daily thus causing inconveniences, and the insulin injection may possibly induce hypoglycemia, which is one of the most serious adverse effects.
While making efforts to remedy these problems, GLP-1 has been on the spotlight recently as the next generation diabetes treatment. GLP-1 and analogs and derivatives thereof have shown good potentials as therapeutic agents for treating type 2 diabetes in clinical trials. They can induce numerous biological effects, such as stimulating insulin secretion, inhibition of glucagon secretion, inhibition of gastric emptying, inhibition of gastric- or intestinal motility, induction of reducing body weight, etc. Additionally, they can protect the pancreas during a long-term administration, are free of hypoglycemia, and maintain appropriate blood glucose levels for a long period of time.
However, GLP-1 is degraded by DPP-4 in-vivo and becomes inactive thereby having a very short half-life in-vivo, which makes it difficult to be developed as a therapeutic agent. Accordingly, various approach methods have been conducted in order to prolong the half-life of GLP-1 or reduce the peptide removal rate from the body while maintaining its biological activities. That is, various GLP-1 analogs have been actively developed, and an approach method to fuse GLP-1 to an immunoglobulin Fc region has been attempted (U.S. Pat. No. 7,452,966 B2, etc.).
Nevertheless, the application of the technology to fuse immunoglobulin Fc has not progressed sufficiently for its commercialization, from the aspect of limitations in half-life, antibody-dependent cell cytotoxicity (ADCC)-inducing capacity, stability for DPP-4 enzyme, etc.
Meanwhile, inflammatory bowel disease (IBD) is thought to occur due to genetic and immunological factors, however, it is an incurable disease in which the causes and treatments still remain to be elucidated. It is a chronic disease caused by the inflammation on the inner wall of the digestive tract, and inflammatory bowel diseases are largely classified into ulcerative colitis and Crohn's disease.
Ulcerative colitis (UC) is a chronic inflammatory disease which occurs on the mucous membrane of the large intestine of the digestive tract, and the inflammation begins from the rectum and is continuously connected to the large intestine. Patients with ulcerative colitis commonly complain of diarrhea, bloody stool, abdominal pain, etc., and symptoms such as anorexia, weight loss, fatigue, etc., are often accompanied as well. In most cases, ulcerative colitis is an intermittent disease repeatedly featuring the periods of exacerbated symptoms and those of ameliorated symptoms, and sometimes there are also long periods that are symptom-free.
In Crohn's disease (CD), unlike ulcerative colitis, inflammation invades the entire layers of the intestine and the distribution of lesions is not continuous but is rather scattered around in many cases. The frequently occurring symptoms of Crohn's disease include diarrhea, abdominal pain, anorexia, etc., but the kinds and degrees of the symptoms vary greatly depending on the patients. In fact, the patients with Crohn's disease appear to experience more severe pain compared to those with ulcerative colitis, and the long-term progress and responses to treatments of the patients with Crohn's disease are much worse, thus often making them undergo surgery.
Although the effective treatment leading to a complete cure of inflammatory bowel disease is still not known because the causes of the inflammatory bowel disease have not been identified yet, studies on the factors affecting the progress of the inflammatory bowel disease have been considerably advanced, and various drugs for reducing inflammation have been developed and are currently in use. The therapeutic agents for inflammatory bowel disease widely used at present are applied sequentially in the order of anti-inflammatory agents (5-aminosalicylic acid; 5-ASA), steroidal agents, immunosuppressive agents such as 6-mercaptopyrine (6-MP), and biological agents such as TNFα inhibitors (anti-TNFα antibody, Infliximab), according to the severity of symptoms. However, these agents currently in use have shown various adverse effects, and accordingly, there is an urgent need for the development of 1) a biological agent having the efficacy to compensate or replace that of the existing drugs, or 2) a biological agent employing a mechanism different from that of the existing drugs.
In an effort to compensate these problems, GLP-2 has been on the spotlight recently as a therapeutic agent for inflammatory bowel disease. GLP-2, which is secreted from the L cells in the intestine, induces the production of IGF-1, nitric oxide (NO), vasoactive intestinal peptide (VIP), etc., through the signaling of GLP-2 receptors expressed in the intestinal cells. The thus-produced IGF-1 induces the growth of the intestinal cells through the signaling of PI-3K and AKT, and NO helps to improve the blood circulation in the intestine. Additionally, since GLP-2 is known to have the anti-inflammatory effect by inducing VIP production, it is also being experimentally confirmed in various research groups that GLP-2 is effective for the treatment of short bowel syndrome as well as for inflammatory bowel disease.
In fact, Gattex® (teduglutide), a GLP-2 analog, was developed by NPS pharmaceuticals, Inc. (USA) at the end of 2012, approved as an orphan drug for the treatment of short bowel syndrome (SBS), and after expanding indications, it is currently in clinical phase 2 studies among patients with inflammatory bowel disease.
However, although Gattex® has a significantly increased half-life compared to that of native GLP-2, it should be also injected once daily, thus still not satisfying unmet needs from the aspect of patient convenience. Furthermore, when the drug is to be applied to inflammatory bowel disease, which is an autoimmune disease requiring lifetime treatment, it should be developed in the form of a long-acting therapeutic agent that can be administered from at least once a week to once a month. That is, since GLP-2 is a peptide hormone, it has a significantly decreased duration compared to that of protein drugs, and thus there is a need for a method of improving the long-term duration of GLP-2.
On the other hand, since cancer cells are characterized by having rapid growth and division, most anticancer agents are designed to kill rapidly growing cells. However, some normal cells also grow rapidly like cancer cells and thus these normal cells are also damaged by anticancer chemotherapy. The rapidly growing and dividing cells among normal cells, i.e., blood cells formed in bone marrow, epithelial cells in the gastrointestinal tract containing oral cavity, hair cells, and germ cells, which produce sperms and ova, are affected more seriously. In particular, anticancer agents frequently cause mucositis in the gastrointestinal tract which may cause diarrhea, and in the case of serious diarrhea, ringer's solution and nutrients should be supplied via intravenous injection to prevent dehydration. In such a case, the preset anticancer chemotherapy schedule may have to be changed thus considerably affecting on cancer treatment. Accordingly, it is considered essential to prevent endoenteritis or diarrhea caused by anticancer chemotherapy in advance because it can reduce the pain of patients while maximizing anticancer effect. In the case of GLP-2, it can induce the proliferation of crypt cells, which form the villi of the small intestine, thereby capable of rapidly recovering from adverse effects due to anticancer chemotherapy, and the development of a GLP-2 analog with a long-term duration can prevent endoenteritis or diarrhea caused by anticancer chemotherapy in advance, by means of one injection for each cycle.
Under these circumstances, the present inventors, in order to develop a long-acting therapeutic agent by increasing the in-vivo half-lives of short-length peptides containing GLP, such as GLP-1 and GLP-2, employed the immunoglobulin hybrid Fc technology disclosed in International Publication No. WO 2008-147143, which was filed previously by the present inventors, selected the immunoglobulin Fc optimized to be specific to glucagon-like peptide (GLP), and prepared a fusion polypeptide with excellent resistance to DPP-4 enzyme while having an increased half-life, thereby completing the present invention.